Allele In Group Research Articles

FOXO3 LONGEVITY GENOTYPE MITIGATES THE IMPACT OF HYPERTENSION ON RISK OF INTRACEREBRAL HEMORRHAGE

Abstract The longevity-associated FOXO3 G allele of SNP rs2802292 is associated with protection against mortality, however the impact of FOXO3 genotype on the association between hypertension and risk of intracerebral hemorrhage (ICH) has not been assessed. Therefore, we utilized the Kuakini Honolulu Heart Program (KHHP), a prospective population-based cohort of Japanese American men living in Hawaii that began in 1965 to study this relation. After excluding baseline prevalent stroke and those missing FOXO3 data, 6,469 men were included in the analysis. Age-adjusted prevalence of ICH by hypertension was assessed for the whole cohort after stratifying by FOXO3 genotype. Cox regression models, adjusted for age, cardiovascular risk factors, FOXO3 and APOE genotypes, were utilized to assess relative risk of hypertension on ICH. All models were created for the whole cohort and stratified by FOXO3 genotype, namely G allele carriers versus TT genotype. Overall, 183 subjects developed ICH over the 34-year follow-up period. Age-adjusted ICH prevalence was 0.90 versus 1.32 per 1,000 person-years follow-up in those without and with hypertension, respectively (p=0.002). After stratifying by FOXO3 genotype, this association was no longer significant in G allele carriers. In the whole cohort, hypertension was an independent predictor of ICH (RR=1.70, 95%CI 1.25, 2.32; p=0.0007). In stratified analyses, hypertension remained an independent predictor of ICH among the FOXO3 TT allele group (RR=2.02, 95% CI 1.33, 3.07; p=0.001), but not in FOXO3 G allele carriers (RR=1.39, 95% CI 0.88, 2.19; p=0.15). Thus, the longevity/resilience-associated FOXO3 G allele may mitigate the impact of hypertension on ICH risk in this population. Further study is needed in other populations.

Alternative splicing and genetic variation of mhc-e: implications for rhesus cytomegalovirus-based vaccines

Rhesus cytomegalovirus (RhCMV)-based vaccination against Simian Immunodeficiency virus (SIV) elicits MHC-E-restricted CD8+ T cells that stringently control SIV infection in ~55% of vaccinated rhesus macaques (RM). However, it is unclear how accurately the RM model reflects HLA-E immunobiology in humans. Using long-read sequencing, we identified 16 Mamu-E isoforms and all Mamu-E splicing junctions were detected among HLA-E isoforms in humans. We also obtained the complete Mamu-E genomic sequences covering the full coding regions of 59 RM from a RhCMV/SIV vaccine study. The Mamu-E gene was duplicated in 32 (54%) of 59 RM. Among four groups of Mamu-E alleles: three ~5% divergent full-length allele groups (G1, G2, G2_LTR) and a fourth monomorphic group (G3) with a deletion encompassing the canonical Mamu-E exon 6, the presence of G2_LTR alleles was significantly (p = 0.02) associated with the lack of RhCMV/SIV vaccine protection. These genomic resources will facilitate additional MHC-E targeted translational research.

The FLT3-ITD Allelic Ratio and NPM1 Mutation Do Not Impact Outcomes in AML Patients with FLT3-ITD after Allo-HSCT: A Retrospective Propensity-Score Matching Study

Introduction: FLT3-ITD occurred in about 25% of adult patients with acute myeloid leukemia (AML), which has been correlated with poor outcomes mainly in cytogenetically normal AML, thus being one of the most frequently affected genes in AML. Whether allogeneic hematopoietic stem cell transplantation (allo-HSCT) can eliminate the detrimental effects of FLT3-ITD mutation in AML patients remain debatable. Studies from our group and others showed that allo-HSCT may overcome the adverse effect of FLT3-ITD on survival outcomes, comparable outcomes were not confirmed in other studies. Additionally, high allelic ratio was correlated with inferior outcomes while NPM1 mutation was associated with favorable outcomes in several studies, but their association with prognosis was not observed in other studies. Previous study from our group showed comparable outcomes between FLT3-ITDmut and FLT3-ITDwt patients, however, the influence of NPM1 mutation and allelic ratio on FLT3-ITDmut patients remains unclear in our database. Hence, we designed a retrospective matched-pair study to compare the survival outcomes between FLT3-ITDmut and FLT3-ITDwt patients who underwent allo-HSCT and further analyzed the impact of NPM1 and allelic ratio on outcomes. Methods: 118 FLT3-ITDmut patients and 497 FLT3-ITDwt patients undergoing allo-HSCT were observed. Each FLT3-ITDmut patients was matched with three FLT3-ITDwt patients using the nearest neighbor-matching method with a caliper size of 0.2. Age and sex of patients, disease status, cytogenetics, pre-MRD, and follow-up days were included in the propensity score model. Results: 116 FLT3-ITDmut patients and 314 FLT3-ITDwt patients were included with a median (range) age of 35 years (1-64). FLT3-ITDmut patients showed higher WBC counts at diagnosis (P<0.001) and NPM1 mutation rate (P<0.001). CIR and LFS of FLT3-ITDmut patients were similar to FLT3-ITDwt patients (CIR:16.9% vs 14.2%, P= 0.266; LFS: 75.1% vs 77.7%, P= 0.399). 32 patients and 41 patients showed NPM1 mutation in FLT3-ITDmut and FLT3-ITDwt patients, respectively. We divided them into four groups based on the status of FLT3-ITD and NPM1 status, no significant difference in CIR and LFS was observed between FLT3-ITDwt NPM1wt, FLT3-ITDwt NPM1mut, FLT3-ITDmut NPM1wt and FLT3-ITDmut NPM1mut patients (FLT3-ITDwt NPM1wt vs FLT3-ITDwt NPM1mut vs FLT3-ITDmut NPM1wt vs FLT3-ITDmut NPM1mut: CIR: 14.8% vs 9.4% vs 16.4% vs 17.8%, P= 0.570; LFS: 76.9% vs 84.4% vs 79.5% vs 67.1%, P= 0.176). 49 patients with available allelic ratio were divided into low allelic ratio (n=25) and high allelic ratio groups (n=24) according to a cut-off 0.50. High allelic ratio was not correlated with inferior outcomes in this study (high allelic ratio vs low allelic ratio: CIR: 21.1% vs 18.1%, P= 0.617; LFS: 70.6% vs 73.7%, P= 0.563). To further analyze the differences between different donor type, we compared the outcomes of 318 haploidentical transplantation and 98 sibling-matched transplantation patients, respectively. FLT3-ITDmut patients had higher CIR and lower LFS than FLT3-ITDwt patients among sibling-matched transplantation (CIR:24.7% vs 12.0%, P= 0.064; LFS:68.2% vs 83.5%, P= 0.0502), but no difference was observed in haploidentical transplantation (CIR: 13.7% vs 15.0%, P= 0.996; LFS:77.8% vs 75.9%, P= 0.885). FLT3-ITD mutation didn't become a prognostic factor in survival outcomes when all patients received transplantation. Prognostic factors with P< 0.1 in univariate analysis were included in multivariate analysis. Apart from pre-MRD, and disease status influencing OS and CIR, another factor affecting OS was the gender of patients. Age played a prognostic role in NRM while pre-MRD and disease status also became the significant factors influencing LFS. Conclusion: Our results showed that allo-HSCT, especially haploidentical HSCT, may overcome the adverse effect of FLT3-ITD mutation, regardless of the NPM1 status or allelic ratio. Allo-HSCT could be an ideal option for AML patients with FLT3-ITD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Major Histocompatibility Complex Class I and Dengue Hemorrhagic Fever: A Meta-Analysis of Human Leukocyte Antigens A*24 and B*44.

Dengue fever (DF) is a disease caused by dengue virus (DENV) from the family Flaviviridae. The role of human leukocyte antigens (HLAs) in dengue fever (DF) and its more severe manifestation, dengue hemorrhagic fever (DHF), has been a topic of great research interest. In addition to HLA profile, race, age, DENV serotype, infection while having certain chronic diseases, and secondary infection are risk factors for DHF susceptibility. Antibody-dependent enhancement (ADE) of dengue virus infection is a mechanism for DHF infection. Individual studies have examined the effects of HLA-A*24 and HLA-B*44 presence on DHF, butnone have analyzed these in a meta-analysis. The objective of this study was to determine the effects of HLA-A*24 and HLA-B*44 presence on DHF and DF susceptibility. A meta-analysis on DHF and DF susceptibility in patients with HLA-A*24 and HLA-B*44 was conducted. Google Scholar was used to find studies that contained patients with HLA-A*24 or HLA-B*44 that were diagnosed with DHF or DF. Studies containing patients diagnosed using the 1997 WHO guidelines and possessing HLA-A*24 or HLA-B*44 that were diagnosed with DHF or DF, including primary or secondary infection, and studies measuring odds ratios (ORs) were included. Patients diagnosed using the 2009 WHO guidelines and studies in a foreign language, using animals, or lacking odds ratios were excluded. The National Institutes of Health (NIH) quality assessment of the case-control study tool was used, and a Doi plot was generated using MetaXL to assess for risk of bias. Review Manager version 5.4 was used to generate odds ratios and forest plots with subgroup analysis from allele and phenotype frequency data. Ten studies from 2001 to 2015 met the inclusion criteria. The studies included 2837 DHF/DF patients and 4880 healthy control (HC) patients. HLA-A*24 was associated with a 1.39 times susceptibility to DHF while those possessing HLA-B*44 were 0.62 times susceptible to DHF (OR=1.39 and 95% CI=1.17-1.66; OR=0.62 and 95% CI=0.39-0.99). NeitherHLA-A*24 nor HLA-B*44 presence was associated with DF susceptibility (OR=1.04 and 95% CI=0.82-1.33; OR=0.88 and 95% CI=0.68-1.14). These results indicate that two different major histocompatibility complex (MHC) class I alleles, HLA-A*24 and HLA-B*44, have opposing effects on DHF susceptibility but none on DF susceptibility. The study's specificity is limited in that it examines HLA allele groups and not specific HLA proteins. The results of this study can be used clinically to identify patients that may be at a higher risk of developing DHF based on their HLA profile.

Genetic variation of LEI0258 locus at major histocompatibility complex (MHC) region in Ethiopian indigenous village chicken

&#x0D; Indigenous chickens are locally adapted to environmental challenges and provide subsistence to millions of farmers in Africa. However, their productivity remains low compared to exotic strains. Efforts are being made to combine the local adaptation of indigenous chicken with productive traits of exotic chicken. Understanding the link between genetic diversity and environmental challenges leads to marker-assisted breed improvement programs for sustainable chicken production at smallholder level. Genetic variation at LEI0258 VNTR locus located within the MHC region has been linked to infectious disease resistance/susceptibility in commercial breeds. The aim of this study was to investigate allelic variability, genetic diversity and genetic relationships of 24 chicken populations in Ethiopia. Here, the diversity at LEI0258 in 236 chickens from 24 Ethiopian indigenous chicken populations using the major Histo-compatibility Complex linked LEI0258 marker is reported. A total of 236 DNA samples were genotyped by capillary electrophoresis from 24 chicken populations. The number of alleles, allele frequency, and heterozygosity levels were used to measure genetic variation at LEI0258 locus in Ethiopian indigenous village chicken. Twenty-nine LEI0258 alleles were observed using capillary electrophoresis that ranged from 185 to 569 bp with no significant difference in allele frequencies between populations. The number of alleles ranged from 179 (Meseret) to 569 (Batambie), with an average of 9.6 alleles per population. Allelic polymorphism was further evaluated through genotyping by Sanger sequencing. Twenty-three DNA samples with different fragment sizes were re-amplified and their alleles sequenced to depict polympormisms based on the combination of two repeat regions at 12 bp and 13 bp, respectively, and flanking regions with SNP and indels. The repeat region at 12 bp appeared 2 to 18 times, whereas the region at 13 bp appeared invariant in all populations. Sequence relationships revealed two distinct groups of alleles. The number of indels and mutations were 33 and 17, respectively. From capillary electrophoresis, the fixation coefficient of the sub-population within the total population (FST), inbreeding/fixation/ coefficient of an individual in a sub population (FIS) and total inbreeding /heterozygosity deficit/ coefficient of an individual within the total population (FIT) in the locus was 0.03, 0.08 and 0.11, respectively. Three percent of the genetic diversity was due to differences among populations, where as 8% and 89% were variations among individuals and variations within individuals, respectively. Despite the overall low genetic differentiation, both fragment and sequencing analysis revealed high allelic and genetic variability across the 24 populations. The high diversity at LEI0258 in Ethiopian indigenous village chicken populations supports the importance of the MHC region in relation to the disease challenges faced by smallholder poultry farmers across Ethiopia. We recommend that breed improvement programs ensure the maintenance of this diversity by selecting breeding stock as diverse as possible at the LEI0258 locus.

Comparative analysis of immunogenetic characteristics of potential hematopoietic stem cell donors from the registries of two Russian megapolises

Efficacy of search for the unrelated compatible transplant donors depends on a number of factors. Of most importance are the standards of primary HLA typing, and the immunogenetic diversity of the donor pool. Timely donor selection guarantees the optimal timing for stem cell transplantation. This factor exerts positive influence upon the transplantation outcomes. In 2019, The Bone Marrow Donors Registry at the Russian Research Institute of Haematology and Transfusiology has implemented HLA-typing for HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1 genes as a standard for primary immunogenetic examination, in order to reduce the donor search period. The aim of our study was to evaluate the HLA typing results for potential stem cell donors at our Registry as compared with immunogenetic profile of donors at the Registries arranged in two Russian megapolises. All currently known groups of HLA-C, HLA-DRB1, HLA-DQB1 gene alleles, 19 of 21 open groups of HLA-A gene alleles, 34 of 36 known groups of HLA-B gene alleles were screened in the donors from our Registry. The most common HLA alleles groups were as follows: A*02 (0.2957), A*03 (0.1432), A*01 (0.1155), A*24 (0.1128); B*07 (0.1282), B*35 (0.1084), B*44 (0.0921), B*18 (0.0745); C*07 (0.2738), C*04 (0.1361), C*12 (0.1202), C*03 (0.1134), C*06 (0.1127); DRB1*15 (0.1445), DRB1*07 (0.1420), DRB1*13 (0.1271), DRB1*01 (0.1269), DRB1*11 (0.1216); DQB1*03 (0.3517), DQB1*06 (0.2269). A total of 1702 HLA-A*-B*-C*-DRB1*-DQB1*-haplotypes were revealed in our donor pool. The frequency of nine HLA-haplotypes exceeded 0.01: A*01-B*08-C*07-DRB1*03-DQB1*02 (0.0366), A*03-B*07-C*07-DRB1*15-DQB1*06 (0.0269), A*03-B*35-C*04-DRB1*01-DQB1*05 (0.0238), A*02-B*13-C*06-DRB1*07-DQB1*02 (0.0204), A*02-B*07-C*07-DRB1*15-DQB1*06 (0.0184), A*25-B*18-C*12-DRB1*15-DQB1*06 (0.0127), A*02-B*18-C*07-DRB1*11-DQB1*03 (0.0126), A*02-B*15-C*03-DRB1*04-DQB1*03 (0.0123), A*02-B*41-C*17-DRB1*13-DQB1*03 (0.0109). We carried out a comparative analysis of the HLA-haplotypes distribution for the donors of three Russian registers: Russian Research Institute of Haematology and Transfusiology (St. Petersburg); First St. Petersburg State I. Pavlov Medical University (St. Petersburg); National Medical Research Center for Hematology (Moscow). The six most common HLA-haplotypes among the donors from three Russian registers had the same rank positions and frequencies. The differences of some less common HLA-haplotypes distribution were determined. The results of our study indicate the immunogenetic diversity of the donor pool the Registry of Russian Research Institute of Haematology and Transfusiology. This fact, along with usage of international standards for primary immunogenetic examination is a prerequisite for effective donor search for the patients requiring stem cell transplantation.

HLA Genotypes in Patients with Infection Caused by Different Strains of SARS-CoV-2.

The aggressive infectious nature of SARS-CoV-2, its rapid spread, and the emergence of mutations necessitate investigation of factors contributing to differences in SARS-CoV-2 susceptibility and severity. The role of genetic variations in the human HLA continues to be studied in various populations in terms of both its effect on morbidity and clinical manifestation of illness. The study included 484 COVID-19 convalescents (northwest Russia residents of St. Petersburg). Cases in which the responsible strain was determined were divided in two subgroups: group 1 (n = 231) had illness caused by genovariants unrelated to variant of concern (VOC) strains; and group 2 (n = 80) had illness caused by the delta (B.1.617.2) VOC; and a control group (n = 1456). DNA typing (HLA-A, B, DRB1) was performed at the basic resolution level. HLA-A*02 was associated with protection against infection caused by non-VOC SARS-CoV-2 genetic variants only but not against infection caused by delta strains. HLA-A*03 was associated with protection against infection caused by delta strains; and allele groups associated with infection by delta strains were HLA-A*30, B*49, and B*57. Thus, in northwest Russia, HLA-A*02 was associated with protection against infection caused by non-VOC SARS-CoV-2 genetic variants but not against delta viral strains. HLA-A*03 was associated with a reduced risk of infection by delta SARS-CoV-2 strains. HLA-A*30, HLA-B*49, and HLA-B*57 allele groups were predisposing factors for infection by delta (B.1.617.2) strains.

Role of insulin receptor substrate-1 polymorphism rs2943641 in the pathogenesis of type 2 diabetes mellitus in the Iraqi population

Insulin receptor substrate-1 is the first and key substrate of the insulin receptor, act as a multisite docking protein for various effector molecules. It is encoded by the IRS-1 gene, which is found on chromosome 2q36.3 in humans. Insulin receptor substrate is an effective insulin signaling agent that plays a key role in preserving the cell’s basic function, any polymorphism in the IRS genes acts as a competitive insulin receptor inhibitor. A total of 150 healthy men as control and 200 diabetic patients participated in this study; it is across-sectional study, patients were chosen while seeking medical care in the outpatient clinic. This study investigates the association of IRS-1 rs2943641 to the pathogenesis of type 2diabetes mellitus in Iraqi males. This study was conducted to study the association of SNP rs2943641[TT(minor allele type), TC(heterozygous alleles type) and CC(major allele type)] to the pathogenesis of type 2diabetes mellitus according to the logistic regression method which demonstrates that there is a significant association between TC and CC allele groups to the pathogenesis of T2DM. In conclusion, genetic polymorphism of IRS-1 rs2943641 is associated with the pathogenesis of T2DM in Iraqi male.

Genetic Variants of HLA-DRB1 Alleles and the Chance of Developing Rheumatoid Arthritis: Systematic Review and Meta-Analysis

Background: Rheumatoid Arthritis (RA) is more common in those who have specific genetic types of Human Leukocyte Antigen (HLA). One of the most important genetic risk factors for RA lies in the HLA-DRB1 locus. Objective: This review aimed to determine which HLA-DRB1 alleles were associated with the risk of RA per allele and phenotype group. Method: Statistical analyses were performed using RevMan version 5.4.1. Results: The meta-analysis included nine articles that involved 3004 RA patients and 2384 healthy controls. In the allele group, the frequencies of three HLA-DRB1 alleles, HLA-DRB1*10 (OR = 1.88, 95%CI = 1.25–2.83, p = 0.002), HLA-DRB1*04 (OR = 2.38, 95%CI = 1.73–3.29, p &lt; 0.00001), and HLA-DRB1*01 (OR = 1.32, 95%CI = 1.08–1.61, p = 0.006), were considerably higher in RA patients than in controls, and these alleles potentially increased the chance of disease development. Five HLADRB1 alleles (*03, *07, *11, *13, and *14), were more prevalent in healthy people than in RA patients and may therefore offer protection against disease onset. Only the DRB1*04 subtypes, DRB1*0401 (OR = 1.37, 95 percent CI = 1.05–1.79, p = 0.02) and DRB1*0404 (OR = 1.73, 95% CI = 1.19–12.53, p = 0.004), showed a significant association with the risk of RA in our pooled effect. Conclusion: Our findings demonstrated a significant relationship between HLA-DRB1 and the risk of RA in various ethnic groups.

Frequency and parameters of linkage disequilibrium of the two-locus &lt;i&gt;HLA-B~MICA&lt;/i&gt; haplotypes in russians from chelyabinsk region

MICA gene is located in the MHC region on chromosome 6p21.33, mapped ca. 46.4 kb centromeric to the HLA-B gene, being in strict linkage disequilibrium with MHC class I region. The sufficient polymorphism of human MICA gene and its location at the HLA region makes it a likely candidate locus for additional histocompatibility testing. The data on distribution of two-locus HLA-B~MICA haplotypes enable us to obtain information about the level of mismatches in the MICA locus when selecting suitable donor-recipient pair by convential HLA loci for unrelated hematopoietic stem cell transplantation. We have performed immunogenetic typing of 100 donors of Russian Nationality from the Register of Stem Cell Donors at Chelyabinsk Regional Blood Bank. MICA genotyping was carried out by PCR tests with sequence-specific primers at basic resolution. Typing of the classical HLA-B locus was carried out by the NGS method using MiSeq instrument using a MiSeq v2 reagent kit (Illumina). Linkage disequilibrium indices D, D`, p, and the frequency of two-locus HLA-B~MICA haplotypes were calculated using Arlequin 3.5 software. As a result of this study, the main parameters of linkage disequilibrium and the frequency of two-locus HLA-B~MICA haplotypes were established for Russians from the Chelyabinsk region. HLA-B allelic groups have been identified that form stable pairs with specific MICA allelic variants (HLA-B*B*07, B*08, B*13, B*14, B* 27, B*37, B*38, B*47, B *48, B*49, B*50, B*52, B*55, B*56, B*57). Moreover, we have revealed HLA-B allelic groups forming highly variable HLA-B~MICA haplotypes (HLA-B*15, B*18, B*35, B*39, B*40, B*41, B*44 and B*51) with increased risk of mismatch for MICA genes. These results could be used in clinical practice in order to assess probability of the donor/recipient mismatch for non-classic MICA locus when selecting potential stem cell donors for hematological patients by HLA testing of classical loci. Moreover, these data could be demanded in population genetics.

Genome-wide marker effect heterogeneity is associated with a large effect dormancy locus in winter malting barley.

Prediction of trait values in plant breeding populations typically relies on assumptions about marker effect homogeneity across populations. Evidence is presented for winter malting barley (Hordeum vulgare L.) germination traits that a single, causative, large-effect gene in the Seed dormancy 1 region on Chromosome 5H, HvAlaAT1 (Qsd1), leads to heterogeneous estimated marker effects genome wide between groups of otherwise related individuals carrying different Qsd1 alleles. This led to reduced prediction accuracy across alleles when a model was trained either on individuals carrying both alleles or one allele. Several genomic prediction models were tested to increase prediction accuracy within the Qsd1 allele groups. Small gains (5-12%) in prediction accuracy were realized using structured genomic best linear unbiased predictor models when information about the Qsd1 allele was used to stratify the population. We concluded that a single large-effect locus can lead to heterogeneous marker effects in the same breeding family. Variance partitioning based on large-effect loci can be used to inform best practices in designing genomic prediction models; however, there are likely few cases for which it may be practical to do this. For malting barley, if germination traits are highly associated with malting quality traits, then similar steps should be considered for malting quality trait prediction.

Pengembangan Epitop PMSA1 Plasmodium falciparum Isolat Lokal Sikka Endemik Malaria

The prevalence of malaria in East Nusa Tenggara Province is relatively high, one of the causes is the genomic polymorphism of Plasmodium Merozoite Surface Antigen 1 (PMSA1) on plasmodium that invades erythrocytes. The development of PMSA1 epitopes for Sikka isolates has not been widely reported, so it is necessary to identify PMSA1 antigens and their epitopes in depth for the design of malaria vaccines. Parasite examination through a microscope, genomic DNA of P. falciparum was isolated then the gene encoding PMSA1 was PCR amplified and cloned using pGEM-Teasy and E. coli TOP'10. Target DNA was confirmed by PCR colony and sequencing, phylogenetic tree construction, and epitope analysis. A total of 15 isolates of genomic DNA and PCR products along ± 1049 bp were detected. The results of the phylogenetic construction showed that PMSA1 was distributed into three allele groups, namely: K1 (8); MAD20 (1); and PMSA1_Sikka (11), dominated by the single PMSA1_Sikka allele. This study has found a different PMSA1 Sikka group with previously identified alleles, strengthened by in silico studies to produce a new candidate antigen epitope from Sikka isolates, immunogenic with a length of 17 aa and predicted to trigger an antibody response.

Polymorphic differences within HLA-C alleles contribute to alternatively spliced transcripts lacking exon 5.

The HLA genes are amongst the most polymorphic in the human genome. Alternative splicing could add an extra layer of complexity, but has not been studied extensively. Here, we applied an RNA based approach to study the influence of allele polymorphism on alternative splicing of HLA‐C in peripheral blood. RNA was isolated from these peripheral cells, converted into cDNA and amplified specifically for 12 common HLA‐C allele groups. Through subsequent sequencing of HLA‐C, we observed alternative splicing variants of HLA‐C*04 and *16 that resulted in exon 5 skipping and were co‐expressed with the mature transcript. Investigation of intron 4 sequences of HLA‐C*04 and *16 compared with other HLA‐C alleles demonstrated no effect on predicted splice sites and branch point. To further investigate if the unique polymorphic positions in exon 5 of HLA‐C*04 or *16 may facilitate alternative splicing by acting on splicing regulatory elements (SRE), in‐silico splicing analysis was performed. While the HLA‐C*04 specific SNP in exon 5 had no effect on predicted exonic SRE, the HLA‐C*16 specific exon 5 SNP did alter exonic SRE. Our findings provide experimental and theoretical support for the concept that polymorphisms within the HLA‐C alleles influence the alternative splicing of HLA‐C.

Modeling and analysis of the Haldane genetic model under Brownian motion using stochastic differential equation

Heterozygote advantage as a natural consequence of adaptation in diploid organisms is an attractive mechanism by which two alleles are maintained in natural populations. It has significant effects on biodiversity conservation and plant and animal breeding programs. The mathematical modeling of this biological mechanism is important for eco-evolutionary dynamics studies and genetics investigations. In this paper, I aimed to formalize the changes of gene frequency in time v(t), and in time and space v(t,x) with additive effects in a birth and death process of the Haldane genetic model using Brownian motion under fluctuations of habitat. In addition, the gene-environment interactions were evaluated under the mechanism. The mathematical model was investigated in both deterministic and white noise forms. It was shown that if the environmental random processes in the Haldane genetic model changed quickly and smoothly, then the diffusion approximation of the allele frequencies could be modeled and analyzed by a stochastic partial differential equation. It was revealed that the mathematical model used in this paper belonged to a more general model. The mathematical model was analyzed and since the modeling by the Cauchy problem had not had a usual global solution, the qualitative behavior of the solutions was considered. Besides, the generalizations of ItÔ integral were defined as the integrals of Wick products of random parameters and noise components. It was found that if v(t,x) behaved like a super-Brownian motion and the fatal mutations took place, as a consequence a tiny group of alleles was quickly disappeared. The v(t,x) was unstable when it was close to one. The stationary phase appeared and v(t,x) tended to the stationary situation in the intermediate region under the stabilizing selection. This was a condition under additive gene effect, but with the presence of dominance gene effect, it might be ambidirectional without considering the epistatic effects. The emergence of the dominance and epistatic effects was due to the directional selection. Since Falconer and MacKay had already introduced a deterministic model to study the frequency of genes with no spatial spreading of the population and no stochastic processes, another model was explained to study their equation in the case of heterozygote intermediate for diffusion approximation of frequency of genes, including white noise. It was shown that if the rates of mutation and selection became very small, then the model would be more deterministic and predictable. On the other hand, if the rates of mutation and selection became large, then the model would be more stochastic, and more fluctuations occurred because of the strong effective noise strength. In this case, the stationary situation did not take place. The outlook can help to model the similar biological mechanisms in eco-evolutionary community genetics for studying the indirect genetic effects via the systems of stochastic partial differential equations, and white noise calculus.

Bullous pemphigoid and milia: prevalence and clinical laboratory findings in a Brazilian sample

BackgroundBullous pemphigoid (BP) associated with milia lesions has been increasingly reported, but its prevalence has not been reported in a Brazilian BP population yet. ObjectivesTo describe the occurrence and clinical-laboratorial findings of BP-milia association in a southeastern Brazilian sample. MethodsA descriptive study based on the medical charts of 102 BP patients was accomplished. Clinical and laboratory data of BP-milia patients were compiled. Total serum IgE measurements, immunoblot assays based on basement membrane zone antigens, and HLA-DQ alleles typing were performed. ResultsMilia was evident in 8 (7.8%) BP patients, five males, aged between 46 and 88 years. Increased total IgE levels were determined in 7 (87.5%) of the eight patients. In five of eight patients, immunoblotting showed IgG reactivity against the BP180-NC16a domain but not against collagen VII or laminin-332; it also revealed reactivity against the BP180 C-terminal domain or LAD-1, or both in four of them. The HLA-DQB1*03:01 and HLA-DQA1*05:05 alleles were identified in three of five BP-milia patients. Moreover, three of five cases presented the HLA-DQB1*06 allelic group. Study limitationsHLA determination was performed in five patients. ConclusionsMilia formation in BP patients seems to be less uncommon than previously admitted. Laboratory data revealed increased IgE; autoantibodies against the BP180 C-terminal domain or LAD-1, or both; and the HLA-DQB1*06 allelic group, described for the BP-milia association. Careful determination of antibodies against basement membrane zone molecules and HLA characterization in different populations may provide further insights into this association.

Wheat glutamine synthetase TaGSr-4B is a candidate gene for a QTL of thousand grain weight on chromosome 4B

Key messageGlutamine synthetase TaGSr-4B is a candidate gene for a QTL of thousand grain weight on 4B, and the gene marker is ready for wheat breeding.A QTL for thousand grain weight (TGW) in wheat was previously mapped on chromosome 4B in a DH population of Westonia × Kauz. For identifying the candidate genes of the QTL, wheat 90 K SNP array was used to saturate the existing linkage map, and four field trials plus one glasshouse experiment over five locations were conducted to refine the QTL. Three nitrogen levels were applied to two of those field trials, resulting in a TGW phenotype data set from nine environments. A robust TGW QTL cluster including 773 genes was detected in six environments with the highest LOD value of 13.4. Based on differentiate gene expression within the QTL cluster in an RNAseq data of Westonia and Kauz during grain filling, a glutamine synthesis gene (GS: TaGSr-4B) was selected as a potential candidate gene for the QTL. A SNP on the promoter region between Westonia and Kauz was used to develop a cleaved amplified polymorphic marker for TaGSr-4B gene mapping and QTL reanalysing. As results, TGW QTL appeared in seven environments, and in four out of seven environments, the TGW QTL were localized on the TaGSr-4B locus and showed significant contributions to the phenotype. Based on the marker, two allele groups of Westonia and Kauz formed showed significant differences on TGW in eight environments. In agreement with the roles of GS genes on nitrogen and carbon remobilizations, TaGSr-4B is likely the candidate gene of the TGW QTL on 4B and the TaGSr-4B gene marker is ready for wheat breeding.

Sequencing of autosomal, mitochondrial and Y-chromosomal forensic markers in the People of the British Isles cohort detects population structure dominated by patrilineages

Short tandem repeat (STR) polymorphisms are traditionally assessed by measuring allele lengths via capillary electrophoresis (CE). Massively parallel sequencing (MPS) reveals differences among alleles of the same length, thus improving discrimination, but also identifying groups of alleles likely related by descent. These may have relatively restricted geographical distributions and thus MPS could detect population structure more effectively than CE-based analysis. We addressed this question by applying an MPS multiplex, the Promega PowerSeq™ Auto/Mito/Y System prototype, to 362 individuals chosen to represent a wide geographical spread from the People of the British Isles (PoBI) cohort, which represents at least three generations of local rural ancestry. As well as 22 autosomal STRs (aSTRs; equivalent to PowerPlex Fusion loci) the system sequences 23 Y-STRs (the PowerPlexY 23 loci) and the control region (CR) of mitochondrial DNA (mtDNA), allowing population structure to be compared across biparentally and uniparentally inherited segments of the genome. For all loci, FST-based tests of population structure were done based on historical, linguistic, and geographical partitions, and for aSTRs the clustering algorithm STRUCTURE was also applied. STRs were considered using both length and sequence. Sequencing increased aSTR allele diversity by 87.5% compared to CE-based designations, reducing random match probability to 1.25E-30, compared to a CE-based 6.72E-27. Significant population structure was detectable in just one pairwise comparison (Central/South East England compared to the rest), and for sequence-based alleles only. The 362 samples carried 308 distinct mtDNA CR haplotypes corresponding to 13 broad haplogroups, representing a haplotype diversity of 0.9985 ( ± 0.0005), and a haplotype match probability of 0.0043. No significant population structure was observed. Y-STR haplotypes belonged to ten broad predicted Y-haplogroups. Allele diversity increased by 33% when considered at the sequence rather than length level, although haplotype diversity was unchanged at 0.999969 ( ± 0.000001); haplotype match probability was 2.79E-03. In contrast to the biparentally and maternally inherited loci, Y-STR haplotypes showed significant population structure at several levels, but most markedly in a comparison of regions subject to Anglo-Saxon influence in the east with the rest of the sample. This was evident for both length- and sequence-based allele designations, with no systematic difference between the two. We conclude that MPS analysis of aSTRs or Y-STRs does not generally reveal stronger population structure than length-based analysis, that UK maternal lineages are not significantly structured, and that Y-STR haplotypes reveal significant population structure that may reflect the Anglo-Saxon migrations to Britain in the 6th century.

Divergent and non-parallel evolution of MHC IIB in the Neotropical Midas cichlid species complex

BackgroundEcological diversification is the result of divergent natural selection by contrasting habitat characteristics that favours the evolution of distinct phenotypes. This process can happen in sympatry and in allopatry. Habitat-specific parasite communities have the potential to drive diversification among host populations by imposing selective pressures on their host's immune system. In particular, the hyperdiverse genes of the major histocompatibility complex (MHC) are implicated in parasite-mediated host divergence. Here, we studied the extent of divergence at MHC, and discuss how it may have contributed to the Nicaraguan Midas cichlid species complex diversification, one of the most convincing examples of rapid sympatric parallel speciation.ResultsWe genotyped the MHC IIB for individuals from six sympatric Midas cichlid assemblages, each containing species that have adapted to exploit similar habitats. We recovered large allelic and functional diversity within the species complex. While most alleles were rare, functional groups of alleles (supertypes) were common, suggesting that they are key to survival and that they were maintained during colonization and subsequent radiations. We identified lake-specific and habitat-specific signatures for both allelic and functional diversity, but no clear pattern of parallel divergence among ecomorphologically similar phenotypes.ConclusionsColonization and demographic effects of the fish could have contributed to MHC evolution in the Midas cichlid in conjunction with habitat-specific selective pressures, such as parasites associated to alternative preys or environmental features. Additional ecological data will help evaluating the role of host–parasite interactions in the Midas cichlid radiations and aid in elucidating the potential role of non-parallel features differentiating crater lake species assemblages.

Tissue-specific genotype-phenotype correlations among USH2A-related disorders in the RUSH2A study.

We assessed genotype-phenotype correlations among the visual, auditory, and olfactory phenotypes of 127 participants with Usher syndrome (USH2) (n =80) or nonsyndromic autosomal recessive retinitis pigmentosa (ARRP) (n = 47) due to USH2A variants, using clinical data and molecular diagnostics from the Rate of Progression in USH2A Related Retinal Degeneration (RUSH2A) study. USH2A truncating alleles were associated with USH2 and had a dose-dependent effect on hearing loss severity with no effect on visual loss severity within the USH2 subgroup. A group of missense alleles in an interfibronectin domain appeared to be hypomorphic in ARRP. These alleles were associated with later age of onset, larger visual field area, better sensitivity thresholds, and better electroretinographic responses. No effect of genotype on the severity of olfactory deficits was observed. This study unveils a unique, tissue-specific USH2A allelic hierarchy with important prognostic implications for patient counseling and treatment trial endpoints. These findings may inform clinical care or research approaches in others with allelic disorders or pleiotropic phenotypes.

SNCA rs3910105 Is Associated With Development of Rapid Eye Movement Sleep Behavior Disorder in Parkinson's Disease.

Background and PurposeRapid eye movement (REM) Rapid eye movement sleep behavior disorder (RBD) is a common non-motor symptom of PD. However, the association between the SNCA rs3910105 genotype and RBD in Parkinson’s disease (PD) remains unclear.MethodsThis study used Parkinson’s Progression Markers Initiative (PPMI) data and included 270 patients with newly diagnosed PD without RBD who were divided into SNCA rs3910105 C carriers (CC+CT; n = 187) and TT carriers (n = 83). They were followed up for 5 years to identify the development of RBD. To investigate the influence of cerebrospinal fluid (CSF) alpha-synuclein (α-syn) and β-amyloid 1–42 (Aβ42) in the association between rs3910105 and RBD, the patients were additionally classified into “high-level” and “low-level” groups using cutoff values for CSF α-syn and Aβ42 levels.ResultsAt baseline, the rs3910105 C allele group had lower CSF α-syn and Aβ42 levels than the TT group. During the 5.0-year follow-up, the rs3910105 C allele group had a higher incidence of RBD than the TT group. In the subgroup analyses, the effect of the rs3910105 C allele was not found in the “low-level” group. However, in the “high-level” group, the rs3910105 C allele independently increased the risk of RBD.ConclusionThe SNCA rs3910105 C allele might be a novel genetic risk factor for RBD development in PD, α-syn pathways might have a role in this association and more basic research would be needed to elucidate the mechanism in the future.